The process of bringing a pharmaceutical to market can take years, and require a substantial capital investment. The required research and clinical trials are lengthy and time-consuming, but the regulatory approval is only the start of what is a complex process to produce and deliver product on a commercial scale. Once the U.S. Food and Drug Administration (“FDA”) approves a drug, pharmaceutical engineers, chemists, and plant managers then prepare the pharmaceutical for mass production.
In pharmaceutical production, the key product to be produced is what is known as the active pharmaceutical ingredient (“API”). Typically, during premarketing development and clinical trials the API has only been produced in very small quantities on a lab bench scale. In a typical pharmaceutical production timeline in the United States a new product application (NDA) is submitted to the FDA (or equivalent regulatory authority in other countries or regions) together with a production process with basic parameters usually developed in the research lab. The process is then further developed for improvement in terms of yield, purity, economics, raw product availability; etc. Subsequently the bench scale “recipe” for the API, which often exists only on paper, must be scaled up to a manufacturing plant scale recipe to accommodate commercial production. The process design for commercial production of a new API can take many months. Once the manufacturing plant scale recipe is developed, the manufacturing process design is developed and tested. Operating instructions are prepared and a recipe is formulated for a production execution system which may comprise a DCS (distributed control system), or an Electronic Work Instruction, or other processor, or any combination of these computer based execution systems. A solvent or water run or dry run (if required), or other offline production simulation run is then effected to fine tune the system before the production campaign (which defines a sequence of one or more batches) is run. Batches of product (active pharmaceutical product or API) are released, with notation of deviations, changes and review. A constant monitoring and analysis of all the manufacturing information is maintained. Deviations from the predicted process design and from quality standards are recorded and investigated both for internal reasons and FDA compliance reasons. Problems with the process design are often uncovered when commercial production challenges emerge over time, and the process may need to be revised and/or the recipe may need to be reformulated until a consistent API product is delivered. All these steps can consume substantial time and expense and must be documented.
Process control systems that produce batches of products typically include a graphical interface, which enables a user (e.g., an engineer) to define and store one or more basic product recipes, batch parameters, equipment lists, etc. These basic product recipes typically include a sequence of process steps that are each associated with or bound to a particular equipment list. In binding recipe process steps to particular pieces of equipment, the user (e.g., an operator) explicitly defines, prior to the batch execution of the recipe, which piece of process control equipment to be used to carry out each process step of the recipe. Additionally, each of the process steps may require a user (e.g., an operator) to define one or more input/output (I/O) batch parameter values that are used during the execution of a batch to control the sequence and/or timing of equipment operations, set alarm limits, set target control values (e.g., set-points), etc. These I/O parameter values may be associated with inputs and outputs that are sent to or which are received from one or more of the field devices within the process control system or, alternatively, may be intermediate or calculated values that are generated by the process control system during the execution of a batch. Thus, in defining a batch, a user (e.g., an operator) typically uses the graphical interface to select a basic product recipe (which includes specifications that bind the process steps of the recipe to process control equipment) and to specify the parameter values that are to be used during execution of the batch.
Once a batch product recipe is perfected, it is exclusive to one plant. Historical differences in product lines at different facilities, combined with years of corporate mergers, spinoffs, and reorganizations, mean that even a single company has manufacturing plants each with a unique collection of equipment and systems, such that a recipe that works in one plant cannot easily be transferred to another plant, due to equipment differences, without substantial re-engineering of the recipe. Although systems have been proposed to automate the commercial scale recipe and process design, they have not delivered a fully enabled, operative system, and thus many of the above steps are typically manually determined and are not automated.
Additionally, manufacturing efficiency programs lead to ever more complex problems of process control and synchronization. Many modern batch process plants run several parallel batches using multiple sets of equipment, or sets of operatively connected control equipment units. Recipes have become more complex, increasing the number of procedural steps. Better real-time measurements of process parameters detect abnormal conditions such as, excess temperature, insufficient pressure, or an unexpectedly high concentration of a particular chemical. Systems desirably respond to these conditions as quickly as possible in order to reduce product loss and to avoid harmful situations.
In addition, government regulation of pharmaceutical batch manufacturing continues to become more exacting. The Food and Drug Administration of the United States (FDA) in 2003 launched the so-called Process Analytic Technology (PAT) initiative. The stated goal of PAT is to control the manufacturing process in addition to final manufactured products. To comply with PAT requirements, manufacturers must be able to assure quality at the intermediate steps of a corresponding manufacturing process and properly and timely respond to detected out-of-specification conditions.
Accordingly, there is a need for a fully integrated process design and management system for process manufacturing which is robustly adapted to operate at both a generic master recipe level and at a specific facility and equipment level.